Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
2000-05-18
2001-08-28
Killos, Paul J. (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C560S041000
Reexamination Certificate
active
06281380
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to the synthesis of N-[N-(3,3-dimethylbutyl)-L-&agr;-aspartyl]-L-phenylalanine 1-methyl ester (neotame) by reductive alkylation and crystallization/isolation in methanol and water. This method of producing neotame results in high purity and is more simple and more economical than the typical preparation of neotame.
2. Related Background Art
N-[N-(3,3-dimethylbutyl)-L-&agr;-aspartyl]-L-phenylalanine 1-methyl ester (neotame) is a high potency dipeptide sweetener (about 8000× sweeter than sucrose) that has the formula
The chemical synthesis of neotame is disclosed in U.S. Pat. Nos. 5,480,668, 5,510,508, 5,728,862 and WO 00/15656, the disclosure of each of which is incorporated by reference herein.
U.S. Pat. No. 5,480,668 describes the formation of neotame in methanol, followed by methanol removal, formation of an aqueous hydrochloric acid solution of the neotame, filtration, drying and recrystallization from an ethanol/water mixture.
U.S. Pat. No. 5,510,508 describes the formation of neotame in aqueous acetic acid and methanol, followed by methanol removal, filtration, drying and washing.
U.S. Pat. No. 5,728,862 describes the formation of neotame in methanol, followed by filtration, washing, methanol reduction, addition of water, methanol distillation, filtration, washing and drying.
WO 00/15656 describes the formation of neotame using Z-aspartame (N-benzyloxycarbonyl-L-&agr;-aspartyl-L-phenylalanine-1-methyl ester) in a methanolic solvent, followed by partial evaporation of the organic part of the solvent, optional addition of water before and/or during and/or after the partial evaporation of the organic part of the solvent, separation of the neotame formed and drying.
In addition to being complicated by various methanol removal and/or distillation steps, these chemical processes may produce several troublesome impurities, including N,N-di(3,3-dimethylbutyl)-L-aspartyl-L-phenylalanine methyl ester (dialkylated aspartame), &agr;-methyl hydrogen-3-( 3,3-dimethylbutyl)-2-L-(2,2-dimethylpropyl)-5-oxo-&agr;-L-(phenylmethyl)-1,4(L)-imidazolidine diacetate (dialkylated imidazolidinone), N-[N-(3,3-dimethylbutyl)-L-&agr;-aspartyl]-L-phenylalanine (demethylated &agr;- or &bgr;-neotame) and methyl ester of N-[N-(3,3-dimethylbutyl)-L-&agr;-aspartyl]-L-phenylalanine 1-methyl ester (methylated &agr;- or &bgr;-neotame). These impurities are represented respectively by the structural formulae:
Since neotame is mainly employed in foods for human consumption, it is extremely important that neotame exist in a highly purified state.
U.S. Pat. No. 5,728,862 outlines a purification method by which neotame is precipitated out of an aqueous/organic solvent solution, wherein the aqueous/organic solvent solution has an amount of organic solvent of about 17% to about 30% by weight.
Copending U.S. patent application Ser. No. 09/448,671, filed on Nov. 24, 1999, relates to methods of purifying neotame by crystallization in a variety of organic solvent/aqueous organic solvent mixtures. Each of these methods which uses an organic solvent and water mixture contemplates a solvent distillation step.
Thus, it is clear that there is a need to economically and efficiently produce pure N-[N-(3,3-dimethylbutyl)-L-&agr;-aspartyl]-L-phenylalanine 1-methyl ester.
SUMMARY OF THE INVENTION
The present invention relates to the efficient, low cost and high purity synthesis of N-[N-(3,3-dimethylbutyl)-L-&agr;-aspartyl]-L-phenylalanine 1-methyl ester. According to the present inventive method, neotame is synthesized by preparing a mixture of aspartame and a catalyst in a solvent consisting of water and methanol; adding 3,3-dimethylbutyraldehyde to the mixture in the presence of hydrogen to produce N-[N-(3,3-dimethylbutyl)-L-&agr;-aspartyl]-L-phenylalanine 1-methyl ester; removing the catalyst; adding water to the mixture to reach a desired crystallization solvent concentration; holding the mixture for a time and at a temperature sufficient to hydrolyze dialkylated imidazolidinone; and crystallizing N-[N-(3,3-dimethylbutyl)-L-&agr;-aspartyl]-L-phenylalanine 1-methyl ester.
In certain preferred embodiments of the present invention, crystallized N-[N-(3,3-dimethylbutyl)-L-&agr;-aspartyl]-L-phenylalanine 1-methyl ester is separated from the mixture.
In a certain embodiment of the present invention, the mixture may be seeded prior to crystallization.
DETAILED DESCRIPTION
The present invention relates to the optimization of the synthesis of N-[N-(3,3-dimethylbutyl)-L-&agr;-aspartyl]-L-phenylalanine 1-methyl ester (neotame) by reductive alkylation in a water/methanol solvent in order to produce substantially pure neotame.
According to the present invention, N-[N-(3,3-dimethylbutyl)-L-&agr;-aspartyl]-L-phenylalanine 1-methyl ester is synthesized by preparing a mixture of aspartame and a catalyst in a solvent consisting of water and methanol; adding 3,3-dimethylbutyraldehyde to the mixture in the presence of hydrogen to produce N-[N-(3,3-dimethylbutyl)-L-&agr;-aspartyl]-L-phenylalanine 1-methyl ester; removing the catalyst; adding water to the mixture to reach a desired crystallization solvent concentration; holding the mixture for a time and at a temperature sufficient to hydrolyze dialkylated imidazolidinone; and crystallizing N-[N-(3,3-dimethylbutyl)-L-&agr;-aspartyl]-L-phenylalanine 1-methyl ester.
According to the first step of the present inventive method, a mixture of aspartame and a catalyst is prepared in a solvent consisting of water and methanol. The ratio of water to methanol in the solvent is from about 5:95 to about 70:30, and preferably from about 30:70 to about 50:50.
The concentration of aspartame in the water and methanol mixture is from about 5% to about 25%, and preferably about 17%. The aspartame used in the present inventive process can be wet with water or dry. Aspartame can also be used in situ from any N-protected aspartame derivative prepared by known methods.
The catalyst suitable for use in the present invention may be selected from catalysts based on palladium or platinum including, without limitation, platinum on activated carbon, palladium on activated carbon, platinum black or palladium black. Other catalysts include, without limitation, nickel on silica, nickel on alumina, Raney nickel, ruthenium black, ruthenium on carbon, palladium hydroxide on carbon, palladium oxide, platinum oxide, rhodium black, rhodium on carbon and rhodium on alumina. The catalysts based on palladium or platinum are preferred.
The catalyst is present in an amount effective to produce neotame in an acceptable yield. Generally, the weight ratio of catalyst (on a dry basis) to aspartame is about 0.01:1 to about 0.25:1, preferably about 0.10:1. It is important to note that about a 10% catalyst loading is required to minimize the undesirable yield of dialkylated aspartame.
According to the second and third steps of the present invention, 3,3-dimethylbutyraldehyde is added to the mixture and reacted with aspartame in the presence of the catalyst and in the presence of hydrogen for a time and at a temperature sufficient to produce neotame. 3,3-Dimethylbutyraldehyde can be added slowly or all at once to the reaction mixture. When the aldehyde is gradually added, typically it is added over the course of about 2 to 8 hours, preferably from about 4 to 6 hours. It is important to note that the reactants, i.e., aspartame, catalyst, aldehyde, can be added in any order.
Aspartame (L-&agr;-aspartyl-L-phenylalanine 1-methyl ester) and 3,3-dimethylbutyraldehyde are readily available starting materials, which are typically combined in a substantially equivalent molar ratio, i.e., about 1:0.95 to 1:1.
Excess molar amounts of aspartame are not preferred due to waste and cost. Higher molar amounts of the aldehyde are likely to lead to the generation of impurities. Further, the 3,3-dimethylbutyraldehyde used in the present process should b
Prakash Indra
Scaros Mike G.
Wachholder Kurt L.
Chaudhry Mahreen
Killos Paul J.
The Nutra Sweet Company
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